Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5+ ve intestinal stem cells survival against lethal radiation injury through Wnt signaling

ABSTRACT The Wnt signaling pathway is deregulated in over 90% of human colorectal cancers. β-Catenin, the central signal transducer of the Wnt pathway, can directly modulate gene expression by interacting with transcription factors of the TCF/LEF family. In the present study we investigate the role of Wnt signaling in the homeostasis of intestinal epithelium by using tissue-specific, inducible β-catenin gene ablation in adult mice. Block of Wnt/β-catenin signaling resulted in rapid loss of transient-amplifying cells and crypt structures. Importantly, intestinal stem cells were induced to terminally differentiate upon deletion of β-catenin, resulting in a complete block of intestinal homeostasis and fatal loss of intestinal function. Transcriptional profiling of mutant crypt mRNA isolated by laser capture microdissection confirmed those observations and allowed us to identify genes potentially responsible for the functional preservation of intestinal stem cells. Our data demonstrate an essential requirement of Wnt/β-catenin signaling for the maintenance of the intestinal epithelium in the adult organism. This challenges attempts to target aberrant Wnt signaling as a new therapeutic strategy to treat colorectal cancer.

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Wnt signaling in adult intestinal stem cells and cancer

Cellular Signalling ◽

10.1016/j.cellsig.2013.11.032 ◽

2014 ◽

Vol 26 (3) ◽

pp. 570-579 ◽

Cited By ~ 216

Author(s):

Michaela Krausova ◽

Vladimir Korinek

Keyword(s):

Stem Cells ◽

Wnt Signaling ◽

Intestinal Stem Cells

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The LPA2 receptor agonist Radioprotectin-1 spares Lgr5-positive intestinal stem cells from radiation injury in murine enteroids

Cellular Signalling ◽

10.1016/j.cellsig.2018.07.007 ◽

2018 ◽

Vol 51 ◽

pp. 23-33 ◽

Cited By ~ 7

Author(s):

Bryan Kuo ◽

Erzsébet Szabó ◽

Sue Chin Lee ◽

Andrea Balogh ◽

Derek Norman ◽

...

Keyword(s):

Stem Cells ◽

Receptor Agonist ◽

Radiation Injury ◽

Intestinal Stem Cells

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Wnt Signaling in Intestinal Stem Cells and Cancer

Reference Module in Biomedical Sciences ◽

10.1016/b978-0-12-801238-3.66182-2 ◽

2018 ◽

Author(s):

Rebecca L. Myers ◽

Maryam Yousefi ◽

Christopher J. Lengner ◽

Peter S. Klein

Keyword(s):

Stem Cells ◽

Wnt Signaling ◽

Intestinal Stem Cells

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Opposing Activities of Notch and Wnt Signaling Regulate Intestinal Stem Cells and Gut Homeostasis

Cell Reports ◽

10.1016/j.celrep.2015.03.007 ◽

2015 ◽

Vol 11 (1) ◽

pp. 33-42 ◽

Cited By ~ 102

Author(s):

Hua Tian ◽

Brian Biehs ◽

Cecilia Chiu ◽

Christian W. Siebel ◽

Yan Wu ◽

...

Keyword(s):

Stem Cells ◽

Wnt Signaling ◽

Intestinal Stem Cells ◽

Gut Homeostasis

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Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis

eLife ◽

10.7554/elife.29538 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 31

Author(s):

Yuhua Tian ◽

Xianghui Ma ◽

Cong Lv ◽

Xiaole Sheng ◽

Xiang Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Radiation Injury ◽

Intestinal Stem Cells ◽

Potential Therapeutic Target ◽

Intestinal Homeostasis ◽

Intestinal Tumorigenesis ◽

Stat3 Signaling ◽

Coordinate Control ◽

Stat3 Signaling Pathway

Intestinal regeneration and tumorigenesis are believed to be driven by intestinal stem cells (ISCs). Elucidating mechanisms underlying ISC activation during regeneration and tumorigenesis can help uncover the underlying principles of intestinal homeostasis and disease including colorectal cancer. Here we show that miR-31 drives ISC proliferation, and protects ISCs against apoptosis, both during homeostasis and regeneration in response to ionizing radiation injury. Furthermore, miR-31 has oncogenic properties, promoting intestinal tumorigenesis. Mechanistically, miR-31 acts to balance input from Wnt, BMP, TGFβ signals to coordinate control of intestinal homeostasis, regeneration and tumorigenesis. We further find that miR-31 is regulated by the STAT3 signaling pathway in response to radiation injury. These findings identify miR-31 as a critical modulator of ISC biology, and a potential therapeutic target for a broad range of intestinal regenerative disorders and cancers.

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